Collagen nano-rod is the ubiquitous brick that endows many tissues with form and structural soundness. Furthermore, collagen molecules constitute a niche that is conducive to cell adhesion, motility, proliferation and biodegradation. That is why, collagen is situated at the center of biomaterial and tissue engineering applications. While the natural collagen-rich tissues have impressive capacity to bear mechanical loads, the mechanical properties of reconstituted collagen has the consistency of a gel; thus, its applications are generally non-load bearing. The major discord between collagen in a native tissue matrix and reconstituted collagen gels is the degree of compaction of the collagen molecules. Fabrication collagen in mechanically robust forms would enable the repair mechanically demanding tissues such as tendons, ligaments, blood vessels, heart valves, trachea, craniofacial and dental tissues.
Tendon-repair procedures occur in excess of 100,000 annually in the U.S. alone costing approximately $30 billion dollars. Such injuries arise from trauma and various degenerative conditions in anatomical locations including the rotator cuff, Achilles tendon and patellar tendon. The incidence is expected to increase with the aging of the population. Often, the injury extends to the bulk of the tendon and is irreparable by suturing.
Tendon injuries may impose grave consequences to the quality of life of an individual. Being the critical unit responsible for transmitting the force generated by the muscles to the bones, an injured tendon results in partial or complete loss in the range of motion of the involved joint. Therefore, repairing gaps to restore the length of the tendon is critical to the success of the surgical repair. Unfortunately, tendons are relatively poorly vascularized limiting their regenerative capacity. Also, tendon regenerates only partially and slowly; animal models of tendon repair where healing is left to occur naturally indicate that the tendon gains 10% of its original strength by 3 months and 50% by 1.5 years. Another issue, particularly with the repair of chronic tendionopathies, is the failure of repair (as high as 20%-95% for the rotator cuff). Cost and suffering associated with repetitive surgeries is a major drawback. Therefore, regenerative solutions which would expedite tendon repair, enable earlier mobilization and reduce failure rates would be highly significant by reducing costs and by improving the range of motion of involved joints.
Suture-based repair is insufficient when a substantial volume of the tendon needs repair, calling for bulk materials for reconstructing the defect. Autografts are the primary choice of surgeons for bulk tendon repair, except that compromising an otherwise healthy tendon for autograft harvest is a major drawback. Morbidity can be associated with donor site. Also, autografts have limited availability. Allografts or xenografts (e.g. porcine skin or subintestinal mucosa) derivatives are other venues for tendon repair. Immune response due to non-collagenous or cellular content, and disease transmission are major concerns for allografts and xenografts. Also, allograft/xenograft performance may be unpredictable because product quality is a function of the donor. Non-degradable synthetic polymers have been used in tendon repair; however, foreign body reaction to these polymers is a significant drawback. It is possible that the optimal solution for tendon repair involves a strategy that will synergize a bioactive scaffold and cells.
Realization of the regeneration of the bulk tendon faces multiple challenges due to the absence of a bioscaffold platform which unifies the following characteristics: a) mechanical competence, b) ability to be populated by cells, c) ability to induce tenogenic differentiation of mesenchymal stem cells (MSCS), AND, d) form and size that can be integrated to the repair site surgically.
Collagen biomolecule is a nanorod which is essentially the basic building block of all load bearing tissues in the body. When collagen monomers are reconstituted, they attain a mechanically inferior gel consistency. Fabrication methods which would process collagen material to mechanically competent and anatomically complex shapes would improve the reconstruction of tendons, bones, joint surfaces, cranial defects, ears, nose and other tissues.
Methods for electrochemical processing of collagen-rich solutions which generate density backed and mechanically robust sheet layers are known.
Recent efforts in the field of tissue engineering to develop scaffolds for cartilage regeneration have shown promise; however, clinical translation of existing scaffolds is limited due to shortcomings in generating cartilaginous tissue that is matching the mechanical properties and the hierarchical structure of native cartilage. Another significant challenge is making these constructs in a fashion to conform to the complex geometry of human joints. An anatomically conforming construct that mimics the composition and mechanical properties of native cartilage would be significant by providing compositional and topographical cues to stimulate chondrogenesis and to promote the formation of neo-cartilage. Cartilage tissue engineering integrates cell-biomaterial complexes to defect site (injectable, solid form scaffolds, scaffold-free strategies etc.). Despite intense studies on tissue engineering of cartilage, there are significant roadblocks.
One challenge is inferior mechanical properties of constructs. Cartilage is a load-bearing tissue and the demand on the mechanical end is significant. Existing scaffolds (such as agarose, synthetic biopolymers etc.) lack mechanical robustness and most studies strategize to attain mechanical rigidity by the synthetic action of the seeded cells during culture period, less so by the scaffolds.
Another challenge is associated with the size of the defect that can be repaired. In general, the majority of existing modalities are limited to repair of early-stage focal defects using flat disc-shaped scaffolds. There are not many technologies which would allow repairing large defects (partial or full joint) expanding over curved planes. To date, other than woven PLA sheets, attempts on large non-conforming defect repair have been limited.
A further challenge is the multiphasic integration where the scaffold needs to conjoin with host cartilage in the periphery and bone at its base. Focal repair scaffolds have not been highly successful in lateral integration with the host cartilage. Partial or total surface replacement may circumvent this issue by limiting the integration problem to the bone at the base of the scaffold.
Scaffolds used in tissue engineering of cartilage are synthetic biopolymers, natural ECM molecules and scaffold-free frameworks formed by cultured cells. Construction of synthetic biopolymers which provide groups conducive to cell adhesion and degradation involves chemical conjugation with associated time and material cost. Scaffold-free strategies have met with some success, but the current challenges involve limited mechanical properties and complex bioreactor conditions to manage the differentiation closely. From a practical point of view, using scaffolds which comprise native cartilage ECM molecules (i.e. type II collagen, glycosaminoglycans, proteoglycans) may be advantageous because these biomolecules present amino acid sequences recognizable by resident cells as well as they can be degraded and remodeled by cells. However, fabricating native molecules in a form and shape that matches the compositional gradient and mechanical robustness of cartilage is a significant challenge.
Transformations of monomeric collagen solutions to solid phase by electrochemical gradients induced by electrodes have been demonstrated.